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The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome

Martínez-Barricarte, Rubén, Heurich-Sevcenco, Meike, López-Perrote, Andrés, Tortajada, Agustin, Pinto, Sheila, López-Trascasa, Margarita, Sánchez-Corral, Pilar, Morgan, Bryan Paul, Llorca, Oscar, Harris, Claire Louise and Rodríguez de Córdoba, Santiago 2015. The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome. Molecular Immunology 66 (2) , pp. 263-273. 10.1016/j.molimm.2015.03.248

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Abstract

Atypical hemolytic uremic syndrome (aHUS) associates with complement dysregulation caused by muta-tions and polymorphisms in complement activators and regulators. However, the reasons why somemutations in complement proteins predispose to aHUS are poorly understood. Here, we have investigatedthe functional consequences of three aHUS-associated mutations in C3, R592W, R161W and I1157T. First,we provide evidence that penetrance and disease severity for these mutations is modulated by inheri-tance of documented “risk” haplotypes as has been observed with mutations in other complement genes.Next, we show that all three mutations markedly reduce the efficiency of factor I-mediated C3b cleavagewhen catalyzed by membrane cofactor protein (MCP), but not when catalyzed by factor H. Biacore anal-ysis showed that each mutant C3b bound sMCP (recombinant soluble MCP; CD46) at reduced affinity,providing a molecular basis for its reduced cofactor activity. Lastly, we show by electron microscopystructural analysis a displacement of the TED domain from the MG ring in C3b in two of the C3 mutantsthat explains these defects in regulation. As a whole our data suggest that aHUS-associated mutations inC3 selectively affect regulation of complement on surfaces and provide a structural framework to predictthe functional consequences of the C3 genetic variants found in patients.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: National Institute of Health
ISSN: 0161-5890
Funders: MRC
Last Modified: 18 Sep 2017 10:23
URI: http://orca-mwe.cf.ac.uk/id/eprint/72301

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Cited 18 times in Scopus. View in Scopus. Powered By Scopus® Data

Cited 5 times in Web of Science. View in Web of Science.

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